Mucosa-associated invariant T-cells (MAIT) are a recently characterized, novel subset of innate-like T-cells that are particularly abundant in the liver and mucosal tissues. MAIT cells express a semi-invariant T cell receptor comprised of V?7.2, limited J? segments (J?2, J?13, or J?20) an limited V? repertoires. Unlike conventional T-cells, MAIT cells recognize microbial metabolites presented by the MHC-1b-related protein MR1, including vitamin B2 (riboflavin) metabolites unique to certain bacteria and fungi. Because of their enrichment in tissues such as the gut, liver and lung, MAIT cells may be particularly important in two aspects of host defense of particular relevance to HIV infection: promoting epithelial integrity and limiting microbial translocation; an responding to opportunistic pathogens such as Mycobacteria, Candida, Salmonella and others. MAIT cell levels in peripheral blood are significantly reduced in chronic HIV infection, as recentl reported by our group and others. We hypothesize that MAIT loss or impairment contributes to persistent immune activation, and compromises host responses to bacterial and fungal pathogens. The overall goals of the project are: (a) to determine the impact of acute and chronic HIV infection on mucosal MAIT cells, and (b) to determine the ability of ART to restore MAIT levels and functionality. IN AIM 1, we will elucidate the basis of MAIT cell loss and dysfunction i chronic HIV infection. We will assess MAIT cell levels and functionality in blood of HIV-infected subjects and controls; address mechanisms by which MAIT cells are lost during chronic HIV infection; and determine the extent to which their antimicrobial functions are restored by antiretroviral therapy (ART). IN AIM 2, we will determine the impact of chronic HIV infection on MAIT cells in terminal ileum and rectal mucosa. We will determine the abundance and functionality of MAIT cells in these tissues, and will address the relationship between MAIT function and immune activation signatures in chronic HIV infection in subjects on and off ART. IN AIM 3, we will determine the dynamics of peripheral and intestinal MAIT cells in acute HIV infection and relate this information to differential disease outcomes and responses to early ART. This project is a collaborative effort involving three Co-PIs and their laboratories: Dr. Barbara Shacklett (contact PI, UC Davis), Dr. Johan Sandberg (Karolinska Institute), and Dr. Michael Eller (HJF/MHRP). The project addresses mechanisms of impaired gastrointestinal mucosal immunity in people with HIV, and is submitted in response to RFA-DK-14-019.